BACKGROUND: Single measurements of plasma Abeta are not useful in the diagnostics of Alzheimer’s disease (AD). However, changes in plasma Abeta levels during repeated testing may be helpful in the prediction and evaluation of progression of the incipient AD or mild cognitive impairment. OBJECTIVE: To examine the relation of baseline and serial plasma Abeta levels to cognitive change in follow-up. METHODS: 269 subjects (52 cognitively impaired and 217 controls) from a population-based cohort were clinically followed up from 3 to 6 years. Serial plasma samples were available from 70 subjects who were followed up for 3 years and 43 subjects followed for 6 years. The plasma Abeta levels were measured using ELISA. RESULTS: Subjects who declined cognitively during the follow-up had lower levels of plasma Abeta42 at the baseline. Plasma Abeta42 and the Abeta42/Abeta40 ratio decreased (-2.4 pg/ml for Abeta42 in 6 years) in those who declined in follow-up, whereas Abeta42 and the Abeta42/Abeta40 ratio increased in the subjects who remained cognitively stable or improved in follow-up. Subjects using acetylsalicylic acid, dipyridamole, antidiabetic or anticoagulant drugs as well as subjects with coronary heart disease had higher levels of Abeta40. CONCLUSIONS: Low or decreasing plasma Abeta42 during the follow-up is associated with cognitive decline. Serial measurement of plasma Abeta42 may be useful in the detection of the subjects who are at risk for cognitive decline.